Noncanonical Cation−π Cyclizations of Alkylidene β-Ketoesters

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Noncanonical Cation−π Cyclizations of Alkylidene β‑Ketoesters: Synthesis of Spiro-fused and Bridged Bicyclic Ring Systems Dylan E. Parsons and Alison J. Frontier* Department of Chemistry, University of Rochester, 414 Huchison Hall, 100 Trustee Road, Rochester, New York 14611, United States

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S Supporting Information *

ABSTRACT: Three cation−π cyclization cascades initiated at alkylidene β-ketoesters bearing pendent alkenes are described. Depending upon the alkene substitution pattern and the reaction conditions employed, it is possible to achieve selective synthesis of the three different types of products, including 1-halo-3-carbomethoxycyclohexanes, spiro-fused tricyclic systems, and [4.3.1] bridged bicyclic ring systems. All three reactions begin with 6-endo addition of an olefin to the alkylidene βketoester electrophile, followed by one of three different cation capture events. corresponding β-ketoester and aldehyde. Experimentation began with the treatment of substrate 1a with Lewis acid promoters, as presented in Table 1. Exposing 1a to 1.1 equiv of AlCl3 promotes cyclization at ambient temperature, affording a 1.7:1 mixture of halide 2a and spirocycle 4a (Table 1, entry 1). Iron halide salts also are effective in promoting the transformation, furnishing either halide 2a or 2b as the major product (entries 2 and 3). The reactivity of Lewis acidic metal halides can be enhanced through the addition of silver hexafluoroantimonate (AgSbF6), which is thought to generate a more cationic metal center through halide abstraction.15 Under these conditions, the formation of halide 2a is suppressed (entries 4, 6, 7). Other metal halides such as gold(III) chloride and magnesium bromide also promote the reaction, although yields are lower than those observed in the analogous iron(III)-promoted cascades. Cyclization attempts were also carried out in the catalytic regime. When the catalyst is prepared from equimolar amounts of FeCl3 and AgSbF6 (loading = 10 mol %), only enone 3 is observed (entry 6). Using a 1:3 ratio of iron to silver (10 mol %/30 mol %), enone 3 dominates unless the reaction temperature is increased to 60 °C, in which case spirocycle 4a is obtained (entry 7). On the other hand, AlCl3 is inefficient as a catalyst; the reactions stall and produce a mixture of halide 2a with trace amounts of 3 along with unreacted starting material (entry 8). These results suggested that it should be possible to obtain either the secondary halides 2 or the spirocycles 4, with good selectivity through application of appropriate reaction conditions. To test this hypothesis, we first carried out a series of experiments designed to produce secondary halide derivatives 2a−m (Scheme 3). Stoichiometric amounts of iron halide salts

C

ascade reactions represent a powerful class of organic transformations that allow for the rapid construction of complex chemical frameworks from linear, achiral systems. Enzyme-controlled cationic cascades are responsible for the assembly of complex terpenoids,1 and synthetic chemists have developed efficient sequences of cation−π cyclizations inspired by these natural processes.2 In the laboratory, these cascade carbocyclizations are initiated upon acidic activation of an alkene,3,4 epoxide,5 acetal,6 or other carbonyl derivative,7 with subsequent propagation or termination via intramolecular capture by a neighboring alkene or aromatic π-system.8 Classically, polyene cyclizations are linear processes proposed to occur through “anti-parallel addition and chairlike folding”2c of a highly ordered intermediate, to deliver fused ring systems in a stereocontrolled manner (Scheme 1, eq 1).9,2b In this manuscript, we describe two novel cation−π cyclization cascades that initiate at an alkylidene β-ketoester group located in the middle of a linear polyene system, enabling diastereoselective assembly of bridged and spiro-fused carbon skeletons (Scheme 1, eqs 2 and 3).10 A third cyclization pathway that terminates with diastereoselective capture of a halogen ion is also described. While α,β-unsaturated carbonyl derivatives can initiate cation-olefin cyclizations,2a only a handful of examples have been reported. These systems, which initially undergo 5-exo (see Scheme 2) or 6-endo cyclization (vide infra) in most cases, do not progress into a typical cation−π cyclization cascade.11 Rather, the reactions generate cationic intermediates that are susceptible to hydride shift pathways (e.g., Scheme 2),12 rearrangements of the carbon skeleton,13 or intramolecular capture by the enolate moiety.14 Our study focuses on the cation−π cyclization pathways of type 1 substrates (Table 1), which contain an unactivated olefin tethered to an alkylidene β-ketoester electrophile. These are easily prepared through Knoevenagel condensation of the © XXXX American Chemical Society

Received: January 8, 2019

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DOI: 10.1021/acs.orglett.9b00094 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 3. Synthesis of Secondary Halides 2a

Scheme 1. Cation−π Cyclization Cascades for Synthesis of Linear-Fused, Spiro-Fused and [4.3.1] Bridged Systems

Scheme 2. 5-exo Cation-Olefin Cyclization/Hydride Shift Sequence with Enone Electrophile

Reaction conditions: FeX3 (1.1 equiv), DCE (0.05 M), 0 °C, 1 h. The E/Z ratio of the alkylidene β-ketoester precursors can be found in the Supporting Information. bAlCl3 used instead of FeCl3. cAlI3 instead of FeCl3, −78 °C instead of 0 °C; DCE = dichloroethane. a

Table 1. Lewis Acid Screening for Tandem Conjugate Addition/Nazarova

entry

acid (equiv)

additive (equiv)

product ratioc (SMb:2:3:4)

1 2 3d 4 5e 6 7f 8

AlCl3 (1.1) FeCl3 (1.1) FeBr3 (1.1) FeCl3 (1.1) FeCl3 (0.1) FeCl3 (0.1) FeCl3 (0.1) AlCl3 (0.1)

− − − AgSbF6 (1.1) − AgSbF6 (0.1) AgSbF6 (0.3) −

0:1.7:0:1 0:4:1:0 2b only 4 only 2:1:4:0 3 only 0:0:1:5 7:1 trace:0

differ at the stereogenic center at the α-position of the βketoester, leading to the tentative structural assignment shown. We next evaluated the versatility of the spirocyclization pathway. The initial screen had indicated that indanones 4 can be obtained using either stoichiometric or catalytic amounts of an FeCl3/AgSbF6 mixture (Table 1, entries 4 and 7). For this study, we exposed both electron-neutral and electron-rich aryl alkylidene β-ketoesters to FeCl3, in combination with AgSbF6 (1:1 ratio or 1:3 ratio), as shown in Scheme 5. For most electron-releasing substrates, the reaction can be achieved in the catalytic regime (20 mol % FeCl3/AgSbF6; 1:1 ratio; formation of 4b−e). Under these conditions, electron-neutral 1a produces 4a in only 17% yield. However, application of 1 equiv of FeCl3/AgSbF6 (1:3) generated 4a in 42% yield. Spirocyclic pyrrole 4f could be prepared using AlCl3 (1 equiv). The results described thus far involve substrates bearing a pendent monosubstituted olefin. Experiments with substrates 5 (Scheme 6), bearing a 1,1-disubstituted alkene, revealed a different cationic cyclization pathway. After some experimentation,17 we found that subjection of 5c to catalytic FeCl3/ AgSbF6 (1:3 ratio) triggered smooth conversion to the [4.3.1] bridged tricyclic system 6c in 70% yield (Table 2, entry 1). Indeed, it was possible to catalyze the tandem cationic cyclization at room temperature using several different Lewis acidic transition metal reagents, with best results obtained using metal halide salts with AgSbF6 as an additive (Table 2, entries 1−5).17 While cyclization with the Cu(II) complex

a

Reaction conditions: Lewis acid (equiv as indicated), DCE (0.05 M), 25 °C, 24 h, 1a (as 5:1 mixture of E/Z isomers). bSM = Starting Material (1a). cRatio determined via 1H NMR analysis. d2 h, 0 °C. e Decomposition was observed. f60 °C; DCE = dichloroethane.

trigger the desired transformation, with both electron-neutral and electron-rich aromatic substrates able to participate (2a− f). Oxygen containing heteroaromatics are also viable substrates, providing the desired products 2h−l. Aluminum trichloride proves to be an effective promoter for nitrogencontaining heteroaromatic precursors, affording 2g and 2m. Finally, magnesium iodide and aluminum iodide are competent promoters for preparation of the secondary iodide 2k. In highly polarized systems,16 the Nazarov cyclization pathway is dominant, with no participation from the pendent olefin (see 2n, Scheme 3). The stereochemistry of the cyclohexanyl halides 2 can be partially deduced using X-ray crystallographic analysis, along with experimental results that provide corroborating data. The two diastereomers (1:1 ratio) of 2d can be separated by column chromatography. When either diastereomer is subjected to basic conditions (Et3N, DCM), the 1:1 mixture is again obtained (Scheme 4). This suggests that the isomers

Scheme 4. Halide 2d: Nature of Diastereomeric Mixture

B

DOI: 10.1021/acs.orglett.9b00094 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 5. Synthesis of Spirocyclic Systems 4a

Table 2. Optimization of Cationic Cyclization Forming [4:3:1] Bridged Systems 6ca

entry

acid (equiv)

additive (equiv)

T (°C)

t (h)

yield (%)

1 2 3

FeCl3 (0.05) CuCl2 (0.1) CuCl2 (0.1)

rt 60 rt

1 2 0.5

70% 69% 68%

4 5 6

InCl3 (0.1) AlCl3 (0.1) HNTf2 (0.5)

AgSbF6 (0.15) AgSbF6 (0.2) AgSbF6 (0.2) HFIP (2) AgSbF6 (0.3) AgSbF6 (0.3) −

rt rt 0

0.5 1 1

61% 62% 17%

a

a

Reaction conditions: FeCl3 (0.2 equiv), AgSbF6 (0.2 equiv), DCE (0.05 M), 60 °C, 2−4 h. bFeCl3 (1 equiv), AgSbF6 (3 equiv), DCE (0.05 M), 25 °C, 3 h. cAlCl3 (1.1 equiv), DCE (0.05 M), 60 °C, 3 h; DCE = dichloroethane.

DCE = dichloromethane.

pattern on the alkene and on the aromatic ring (Scheme 6). Electron-rich aromatic rings readily cyclize to furnish 6a and 6b. In general, heteroaromatic systems also participate in the cyclization, affording 6c−6g. Different substitution patterns on the alkene are also tolerated, leading to the assembly of bridged systems 6c and 6h−6m, with installation of an all-carbon quaternary center at the bridgehead position. Comparing 6h− 6j, it appears that increased steric bulk correlates with a decreased yield, presumably due to congestion during the Friedel−Crafts step. In substrates with longer tethers, the initial cation−π cyclization occurs, but the Friedel−Crafts trapping does not, and the cationic intermediate decomposes to a complex mixture of inseparable products. Substrates with shorter tether lengths do not cyclize at all. The different cationic cyclization reaction outcomes observed in the formation of halides 2, spirocyclic indanones 4, and bridged [4.3.1] systems 6 can be rationalized as outlined in Scheme 7. All three pathways begin with nucleophilic attack of the terminal carbon of the olefin onto the distal carbon of the alkylidene β-ketoester (6-endo cyclization), facilitated by the

Scheme 6. Scope of Formal [5 + 2] Cycloaddition Reactionsa

Scheme 7. Mechanistic Hypothesis

a

Reaction conditions: CuCl2 (0.1 equiv), AgSbF6 (0.2 equiv), DCE (0.05 M), 60 °C, 2 h; DCE = dichloroethane.

required elevated temperatures (entry 2), addition of 2 equiv of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) induced efficient cyclization at ambient temperature (entry 3).18 Inefficient cyclization is observed in protic acid (entry 6). The copper(II) chloride/silver hexafluoroantimonate combination (Table 2, entry 2) was chosen for examination of the substrate scope (Scheme 6). The cationic cyclization of aromatic alkylidene β-ketoesters 5 show a reasonably broad substrate scope, especially with respect to the substitution C

DOI: 10.1021/acs.orglett.9b00094 Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

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Lewis acid catalyst. This cyclization generates the cationic species CC1, an intermediate common to all three reaction pathways. When a type 1 substrate is treated with stoichiometric amounts of a metal(III) halide, CC1 is trapped by the halide anion in a highly diastereoselective manner, generating type 2 products. Halide addition in related cation−π cyclizations is proposed to occur through a concerted mechanism, installing the halide trans to the new C−C bond.19 The enolate is then protonated to give products 2 as a 1:1 mixture of diastereomers, epimeric at the α-position of the β-ketoester. The spirocyclic products 4 are produced when intermediate CC1 undergoes two sequential [1,2]-Wagner−Meerwein hydride shifts (cf. Scheme 2),12 eventually generating stabilized tertiary carbocation CC2, which undergoes Nazarov cyclization to give spirocycles 4 (cf. Scheme 1, eq 2). Consistent with this mechanistic proposal, aryl enone 3 can be isolated if the reaction is stopped before the cascade is complete. Furthermore, if 3 is resubjected to the reaction conditions, it cyclizes. [4.3.1] Bridged bicyclic products 6 are formed when intermediate CC1 engages in an intramolecular Friedel−Crafts alkylation. This occurs when CC1 is a tertiary carbocation, and the [1,2]-hydride shift pathway is disfavored relative to the direct capture of the stabilized cation with the electron-rich aromatic ring. With these results, we demonstrate that alkylidene βketoesters bearing pendent olefins can engage in three distinct reaction pathways, each of which can be accessed with complete selectivity. In two cases, a novel cationic cascade converts a simple aromatic precursor into an unusual, threedimensional carbocyclic scaffold containing an all-carbon quaternary center (i.e., 4 and 6). In the synthesis of spirocycles 4, two new C−C bonds are formed at the same carbon of the reactant (i.e., the β-position of alkylidene β-ketoesters 1). In the assembly of [4.3.1] bridged bicyclic systems 6, two new C−C bonds are formed diastereoselectively, in a formal [5 + 2] cyclization process.20 These cyclizations represent expansions to the canon of cation-olefin and polyene cyclizations, producing irregular patterns of ring fusions rather than the typical, linear-fused polycyclic systems.

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Letter

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Alison J. Frontier: 0000-0001-5560-7414 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the National Science Foundation (CHE1565813) for funding this research. We also thank William W. Brennessel (University of Rochester) for X-ray crystallography and Kevin Well (University of Rochester Medical Center) for high-resolution mass-spectrometric analysis.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00094. Preparation of alkylidene β-ketoester starting materials, general procedure for halide trapped products, general procedure for the formation of spirocyclic products, optimization of formal [5 + 2], general procedure for formal [5 + 2] (PDF) Accession Codes

CCDC 1889265 and 1889268 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. D

DOI: 10.1021/acs.orglett.9b00094 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters were required precursors for these cyclizations) . (d) Graham, M.; Baker, R. W.; McErlean, C. S. P. Eur. J. Org. Chem. 2017, 2017, 908− 913 (a mixture of fused and bridged products is obtained) . (e) Yeh, M. C. P.; Liang, C. J.; Fan, C. W.; Chiu, W. H.; Lo, J. Y. J. Org. Chem. 2012, 77, 9707−9717. (f) Zhang, Q.; Tiefenbacher, K. Nat. Chem. 2015, 7, 197−202. (g) Catti, L.; Pöthig, A.; Tiefenbacher, K. Adv. Synth. Catal. 2017, 359, 1331−1338. (h) Minassi, A.; Pollastro, F.; Chianese, G.; Caprioglio, D.; Taglialatela-Scafati, O.; Appendino, G. Angew. Chem., Int. Ed. 2017, 56, 7935−7938 (Nazarov initiated cation−π cyclization) . (11) Nazarov cyclization of dienones can initiate cation-π cyclization cascades: see (a) Bender, J. A.; Arif, A. M.; West, F. G. J. Am. Chem. Soc. 1999, 121, 7443−7444. (b) Bender, J. A.; Blize, A. E.; Browder, C. C.; Giese, S.; West, F. G. J. Org. Chem. 1998, 63, 2430−2431. (12) (a) Snider, B. B.; Rodini, D. J.; Van Straten, J. J. Am. Chem. Soc. 1980, 102, 5872−5880. (b) Breitler, S.; Han, Y.; Corey, E. Org. Lett. 2017, 19, 6686−6687. (13) (a) Amupitan, J. A.; Huq, E.; Mellor, M.; Scovell, E. G.; Sutherland, J. K. J. Chem. Soc., Perkin Trans. 1 1983, 751−753. (b) Amupitan, J. A.; Scovell, E. G.; Sutherland, J. K. J. Chem. Soc., Perkin Trans. 1 1983, 755−757. (c) Amupitan, J. A.; Beddoes, R. L.; Mills, O. S.; Sutherland, J. K. J. Chem. Soc., Perkin Trans. 1 1983, 759− 763. (d) Chou, H. H.; Wu, H. M.; Wu, J. D.; Ly, T. W.; Jan, N. W.; Shia, K. S.; Liu, H. J. Org. Lett. 2008, 10, 121−123. (e) Hsieh, M. T.; Chou, H. H.; Liu, H. J.; Wu, H. M.; Ly, T. W.; Wu, Y. K.; Shia, K. S. Org. Lett. 2009, 11, 1673−1675. (14) (a) Harding, K. E.; Cooper, J. L.; Puckett, P. M.; Ryan, J. D. J. Org. Chem. 1978, 43, 4363−4364. (b) Majetich, G.; Khetani, V. Tetrahedron Lett. 1990, 31, 2243−2246. (c) Liu, H. J.; Sun, D.; Shia, K. S. Tetrahedron Lett. 1996, 37, 8073−8076. (15) For selected examples in which AgSbF6 is used to increase the cationic character of a metal center, see: (a) Bernardi, A.; Colombo, G.; Scolastico, C. Tetrahedron Lett. 1996, 37, 8921−8924. (b) Jin, T.; Yamamoto, Y. Org. Lett. 2007, 9, 5259−5262. (c) Vaidya, T.; Cheng, R.; Carlsen, P. N.; Frontier, A. J.; Eisenberg, R. Org. Lett. 2014, 16, 800−803. (d) Leboeuf, D.; Huang, J.; Gandon, V.; Frontier, A. J. Angew. Chem., Int. Ed. 2011, 50, 10981−10985. (e) Jefferies, L. R.; Cook, S. P. Org. Lett. 2014, 16, 2026−2029. (16) He, W.; Herrick, I. R.; Atesin, T. A.; Caruana, P. A.; Kellenberger, C. A.; Frontier, A. J. J. Am. Chem. Soc. 2008, 130, 1003− 1011. (17) Full details of the optimization are provided in the Supporting Information. (18) Colomer, I.; Chamberlain, A. E. R.; Haughey, M. B.; Donohoe, T. J. Nat. Rev. Chem. 2017, 1, 0088. (19) Snider, B. B.; Roush, D. M. J. Org. Chem. 1979, 44, 4229−4232. (20) Shenje, R.; Martin, M. C.; France, S. Angew. Chem., Int. Ed. 2014, 53, 13907−13911.

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DOI: 10.1021/acs.orglett.9b00094 Org. Lett. XXXX, XXX, XXX−XXX